COpenhagen Magnetic Personalized Accelerated Brain Circuit Therapy for Treatment Resistant Depression

Официальное название

The Copenhagen Magnetic Personalized Accelerated Brain Circuit Therapy (CoMPACT) Trial

Обзор

The CoMPACT trial is a randomized double-blinded sham-controlled study aimed at testing a novel accelerated and personalized transcranial Magnetic Stimulation (TMS) treatment for patients with Treatment Resistant Depression (TRD). CoMPACT consists of 25 sessions of intermittent theta-burst transcranial stimulation (iTBS) consisting of high inter-pulse frequency administered five times daily over five consecutive days. The trial will include 78 patients with TRD who will be randomly assigned to one of three groups: * Group 1: Real CoMPACT targeting the left dorsolateral prefrontal cortex (DLPFC). * Group 2: Real CoMPACT targeting a novel site, the left inferior parietal lobule (IPL). * Group 3: Sham CoMPACT targeting the left DLPFC (50%, Group 3a) or left IPL (50%, Group 3b). The hypothesis is that real prefrontal or parietal CoMPACT targeting will significantly alleviate depression symptoms compared to sham targeting, without compromising safety, feasibility, or tolerability. The trial incorporates a personalized approach, using electrical field (E-field) modeling based on individual structural brain scans to tailor and standardize iTBS, ensuring accurate targeting of cortical volume and consistent induced electrical field strength. To delineate the treatment mechanism of action at the brain network level, multi brain mapping models will be implemented. Electroencephalography (EEG) records of spontaneous and TMS-evoked electrical brain activity will be obtained before, during, and after iTBS sessions to understand how the high frequency burst protocol functionally engages the stimulated cortex. Structural and functional brain MRI before and after the treatment will be used to study changes in depression-related brain networks. This will offer key insights into how CoMPACT affects depression-related brain networks and may identify neuroimaging markers for predicting treatment response, and thus informing future TBS treatments for TRD.

Подробное описание

Repetitive TMS (rTMS) of left DLPFC was approved by the US Food and Drug Administration (FDA) in 2008 as a therapy TRD, and this was extended to the equally effective iTBS protocol in 2018.

Dysfunctional connectivity between the left DLPFC and subgenual anterior cingulate cortex (sgACC) has been implicated in the pathogenesis of depression. It has been hypothesized that rTMS-induced neuroplasticity in left DLPFC modifies functional connectivity between left DLPFC and sgACC, normalizing the underlying brain circuit dysfunction.

A recent development has been a move towards "accelerated" rTMS protocols with more than one session per day. Recently, two studies reported promising results for the Stanford Accelerated Intelligent Neuromodulation Treatment (SAINT) protocol for TRD.

The aim of the COMPACT trial is to introduce and test a novel accelerated iTBS therapy for TRD that is designed to significantly expand existing work on accelerated iTBS.

The novel CoMPACT protocol utilizes high frequency bursts to produce a strong "acceleration" effect, securing therapeutic efficacy and clinical feasibility.

The COMPACT protocol consists of five iTBS sessions per day (rather than 10 sessions per day as given in the "SAINT" protocol) over five consecutive days to increase feasibility. In addition to accelerated iTBS of left DLPFC, the invetigators will test clinical efficacy of a novel parietal target, the left IPL. The investigators hypothesize that accelerated iTBS of the area in left IPL that shows a strong negative functional connectivity with the sgACC will be also highly effective in treating TRD compared to the accelerated sham protocol.

Anatomically guided personalized targeting and dosing will be based on E-field modeling informed by the individual cortical anatomy revealed by the patient's structural brain MRI.

Patients with TRD are recruited from psychiatric departments in Copenhagen. Information material with contact details for the project will be available in waiting rooms at the outpatient clinics so that potential participants can contact the project themselves. Furthermore, we will recruit by advertising via Trialtree.dk After inclusion, participants will undergo a baseline assessment (T0) that includes evaluating depression severity and several widely used psychiatric rating scales measuring anhedonia, cognitive deficits, and treatment-related adverse effects. A list of the tests included can be found in the "Outcome" section.

Within two weeks after T0, patients will undergo 5 days of active iTBS targeting either the left DLPFC or the left IPL, or a sham intervention on the left DLPFC or IPL, for a total of 25 sessions. During the first and last day of intervention week, EEG will be used recorded before, during and after first and last iTBS sessions. This helps to investigate acute changes in the cortical activity patterns induced by a single iTBS and the cumulative functional effects on cortical activity caused by the CoMPACT protocol.

Moreover, EEG response to a single and multi TMS pulse, so-called transcranial evoked potentials (TEPs), will be measured before and after iTBS session. This will allow us to explore how high-frequency burst iTBS modulates cortical excitation and inhibition in targeted regions and its potential correlation with clinical response. Online EEG monitoring during iTBS will be performed can also be used to document safety and capture brain activity during the periods separating consecutive iTBS trains.

The antidepressive effects of the intervention (Hamilton Depression Rating Scale as primary outcome) will be assessed, within 3 days after the last session. The rest of the clinical tests will be performed within 5 days after end of treatment (T1). The long-term effect on symptom of depression and other clinical effect will be tested after 4 weeks (T2) and at potential 6 months follow-up.

Assessments at T0 and T1 will also include structural (T1 and T2 weighted sequences), diffusion sensitive MRI, resting-state, and task-based functional MRI (fMRI). Task-related fMRI will reveal how the active CoMPACT intervention modifies brain activity and connectivity within key brain networks compared to sham COMPACT. Cognitive performance will be also probed using a selected set of cognitive tests at T0, T1 and T2.Referral to standard TMS therapy for non-responders:

If patients have not entered remission (i.e. a score less than 7 on HDS-17) immediately after the end of COMPACT treatment or at visit T1, they will be offered standard TMS treatment. A treatment that is approved for general clinical use in psychiatric wards and elsewhere.

Data will be collected at the participating sites in the Capital Region of Denmark (RegionH). After end of trial and final data analysis, anonymized trial-related data and methods will be made available to other researchers through public databases after publication of the main clinical outcome paper in accordance with Danish law.

Вмешательства

• Устройство MagVenture XP Orange Stimulator and active side of MagVenture COOL-B65 coil.
  Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (DLPFC) will be administered over five consecutive days. On each intervention day, patients will undergo five high frequency iTBS sessions (each lasting approximately 10 minutes, excluding preparation) with about 50 minutes of rest between sessions. Each iTBS session delivers 1,800 pulses, resulting in a total of 25 sessions and 45,000 pulses over the course of a standard work week.
• Устройство Device: MagVenture XP Orange Stimulator and active side of MagVenture COOL-B65 coil.
  Intermittent theta burst stimulation (iTBS) targeting the left inferior parietal lobule (IPL) will be administered over five consecutive days using the stimulation pattern described in the active DLPFC arm.
• Устройство Sham stimulation of the MagVenture MagPro XP Orange Edition Prototype flipping the active side of the MagVenture Cool-B65 coil
  Device: Sham stimulation of the left DLPFC or IPL will be administered using the same stimulation duration and repetition as the active iTBS. To match the subjective experience of iTBS, the sham CoMPACT uses a dedicated (Active/Placebo) stimulation coil that has both active and sham functions, generating the same sound level regardless of the type of stimulation.

Первичные конечные точки

• Change in the Hamilton Rating Scale for Depression-6 (HDS-6) Score [Срок оценки: 1) Baseline T0: (1 (+1) week before intervention. 2) Before the first iTBS session on the first day of intervention week. 3) A day after end of intervention (+2 days). 4) Follow-up (T2): 4 weeks after end of intervention.]

Вторичные конечные точки (12)

• Change in the Hamilton Rating Scale for Depression-17 (HDS-17) Score [Срок оценки: 1) Baseline T0: (1 (+1) week before intervention. 2) Before the first iTBS session on the first day of intervention week. 3) A day after end of intervention (+2 days) . 4) Follow-up (T2): 4 weeks after end of intervention.]
• Change in the WHO-5 Well-being Index (WHO-5) score [Срок оценки: 1) Baseline T0: (1 (+1) week before intervention. 2) Postintervention (T1): 3 (+/-2 ) days after end of intervention. 3) Follow-up (T2): 4 weeks after end of intervention.]
• Change Snaith-Hamilton Pleasure Scale (SHAPS) score [Срок оценки: 1) Baseline T0: (1 (+1) week before intervention. 2) Postintervention (T1): 3 (+/-2 ) days after end of intervention. 3) Follow-up (T2): 4 weeks after end of intervention.]
• Change in Overall Anxiety Severity and Impairment Scale (OASIS) score [Срок оценки: 1) Baseline T0: (1 (+1) week before intervention. 2) Postintervention (T1): 3 (+/-2 ) days after end of intervention. 3) Follow-up (T2): 4 weeks after end of intervention.]
• Visual analogue mood scale (VAMS) [Срок оценки: 1) Baseline T0: (1 (+1) week before intervention. 2) On every day of intervention. 3) Postintervention (T1): 3 (+/-2 ) days after end of intervention. 4) Follow-up (T2): 4 weeks after end of intervention.]
• Change in functionality Assessment Short Test (FAST) score [Срок оценки: 1) Baseline T0: (1 (+1) week before intervention. 2) Postintervention (T1): 3 (+/-2 ) days after end of intervention. 3) Follow-up (T2): 4 weeks after end of intervention.]
• Change in Pittsburgh Sleep Quality Index (PSQI) score [Срок оценки: Baseline T0: (1 (+1) week before intervention., Postintervention (T1): 3 (+/-2 ) days after end of intervention. Follow-up (T2): 4 weeks after end of intervention.]
• TMS Sensation Questionnaire (TMSens_Q) [Срок оценки: Intervention week: before and after the first and last sessions on both days 1 and 5]
• Screening for Cognitive Impairment in Psychiatry (SCIP) [Срок оценки: 1) Baseline T0: (1 (+1) week before intervention. 2) Postintervention (T1): 3 (+/-2 ) days after end of intervention. 3) Follow-up (T2): 4 weeks after end of intervention.]
• Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) score [Срок оценки: 1) Baseline T0: (1 (+1) week before intervention. 2) Postintervention (T1): 3 (+/-2 ) days after end of intervention. 3) Follow-up (T2): 4 weeks after end of intervention.]
• Aarhus Side effect Assessment Questionnaire (ASAQ) [Срок оценки: Baseline T0: (1 (+1) week before intervention. Postintervention (T1): 3 (+/-2 ) days after end of intervention. Follow-up (T2) 4 weeks after end of intervention.]
• Young Mania Rating scale (YMRS) [Срок оценки: Intervention week: before the first session on Day 1 and at the end of each intervention day.]

Критерии участия

Критерии включения

• Age range between 18 and 95 years
• In- or outpatients with a moderate to severe single episode or periodic MDD according to ICD-10, verified by a M.I.N.I. interview.
• Major Depression Inventory (self-rapport) score higher than 25.
• Lacking or insufficient effect of at least two drug trials from two distinct classes, e.g., SSRI, SNRI, TCA, or MAO-inhibitors, used in the current episode, with adequate dose and duration as judged by the investigator.
• Duration of the current episode must be longer than 2 months but shorter than 4 years, as judged by the investigator.

Критерии исключения

• History of neurologic disease affecting the brain, including dementia and epilepsy
• Schizophrenia or any other psychotic disorder except for psychotic depression
• Head trauma causing more than 5 minutes loss of consciousness
• Suicidal or psychotic symptoms making the transport of participants hazardous
• Any form of compulsory admission or treatment within the past three months
• Treatment with ECT in the current depressive episode
• Non-responders to TBS treatment within the current episode
• Current harmful use or dependency of substances according to ICD-10 and interfering with outcome evaluation as judged by investigator's discretion.
• High risk of non-adherence as judged by investigators discretion
• Medical and psychiatric conditions interfering with study outcome and safety as judged by investigator's discretion.
• Female participants of childbearing age must not be pregnant or breast feeding, and they must use contraception during the trial.
• One of the prime contra-indications for MRI, including severe claustrophobia (see Appendix 08.05)
• One of the prime contra-indications for TMS and persons with electrically, magnetically, or mechanically activated implants or with metal or magnetic pieces in their head (see Appendix 08.04)
• Patients who do not wish to be informed about MRI or EEG findings, which may have clinical relevance.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Дания · 3 центра

• Centre of Neuropsychiatric Depression Research — Glostrup Municipality
• Mental Health Center North Zealand — Hilleroed
• Danish Research Centre for Magnetic Resonance — Hvidovre

Публикации

• Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, Veerapal C, Khan N, Cherian K, Felber E, Brown R, Choi E, King S, Pankow H, Bishop JH, Azeez A, Coetzee J, Rapier R, Odenwald N, Carreon D, Hawkins J, Chang M, Keller J, Raj K, DeBattista C, Jo B, Espil FM, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. PMID 34711062
• Cole EJ, Stimpson KH, Bentzley BS, Gulser M, Cherian K, Tischler C, Nejad R, Pankow H, Choi E, Aaron H, Espil FM, Pannu J, Xiao X, Duvio D, Solvason HB, Hawkins J, Guerra A, Jo B, Raj KS, Phillips AL, Barmak F, Bishop JH, Coetzee JP, DeBattista C, Keller J, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Am J Ps PMID 32252538
• Voigt JD, Leuchter AF, Carpenter LL. Theta burst stimulation for the acute treatment of major depressive disorder: A systematic review and meta-analysis. Transl Psychiatry. 2021 May 28;11(1):330. doi: 10.1038/s41398-021-01441-4. PMID 34050123
• Kan RLD, Padberg F, Giron CG, Lin TTZ, Zhang BBB, Brunoni AR, Kranz GS. Effects of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex on symptom domains in neuropsychiatric disorders: a systematic review and cross-diagnostic meta-analysis. Lancet Psychiatry. 2023 Apr;10(4):252-259. doi: 10.1016/S2215-0366(23)00026-3. Epub 2023 Mar 7. PMID 36898403
• Ressler KJ, Mayberg HS. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat Neurosci. 2007 Sep;10(9):1116-24. doi: 10.1038/nn1944. PMID 17726478
• Fox MD, Buckner RL, White MP, Greicius MD, Pascual-Leone A. Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol Psychiatry. 2012 Oct 1;72(7):595-603. doi: 10.1016/j.biopsych.2012.04.028. Epub 2012 Jun 1. PMID 22658708
• Cash RFH, Weigand A, Zalesky A, Siddiqi SH, Downar J, Fitzgerald PB, Fox MD. Using Brain Imaging to Improve Spatial Targeting of Transcranial Magnetic Stimulation for Depression. Biol Psychiatry. 2021 Nov 15;90(10):689-700. doi: 10.1016/j.biopsych.2020.05.033. Epub 2020 Jun 7. PMID 32800379

Идентификаторы

NCT: NCT06895863 · CoMPACT · 10.46540/3166-00150B · Precision-BCT - 9068-00025A

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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